Imidazolyl thioureas, ureas and guanidines

ABSTRACT

The compounds are N,N&#39; -substituted thioureas, ureas and guanidines which are H-2 histamine receptor inhibitors. Two compounds of this invention are N,N&#39;-bis[2-((4-methyl-5-imidazolyl)methylthio)ethyl] thiourea and N,N&#39;-bis[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-N&#39;&#39;-cyanoguanidine.,

This is a division of application Ser. No. 640,525 filed Dec. 15, 1975,now U.S. Pat. No. 4,025,527 which is a continuation-in-part of Ser. No.481,716 filed June 21, 1974, now abandoned.

This invention relates to pharmacologically active N,N'-substitutedthioureas, ureas and guanidines. These compounds are inhibitors of H-2histamine receptors. In addition, this invention relates topharmaceutical compositions and methods of inhibiting H-2 histaminereceptors with these compounds.

The compounds of the invention can exist as the addition salt but, forconvenience, reference will be made throughout this specification to theparent compounds.

It has long been postulated that many of the physiologically activesubstances within the animal body, in the course of their activity,combine with certain specific sites known as receptors. Histamine is acompound which is believed to act in such a way but, since the actionsof histamine fall into more than one type, it is believed that there ismore than one type of histamine receptor. The type of action ofhistamine which is blocked by drugs commonly called "antihistamines" (ofwhich mepyramine is a typical example) is believed to involve a receptorwhich has been designated as H-1. A further group of substances has beendescribed by Black et al. (Nature 1972, 236, 385) which aredistinguished by the fact that they act at histamine receptors otherthan the H-1 receptor and these receptors have been designated as H-2receptors. This latter group of substances, to certain of which thepresent invention relates, are thus of utility in inhibiting certainactions of histamine which are not inhibited by the above-mentioned"antihistamines", that is they are H-2 histamine receptor inhibitors.Inhibitors of H- 2 histamine receptors, which are also referred to ashistamine H-2 antagonists, are useful for example, as inhibitors ofgastric acid secretion, as anti-inflammatory agents and as agents whichact on the cardiovascular system, for example as inhibitors of theeffects of histamine on blood pressure. The histamine H-2 antagonists ofthis invention may also be of utility as inhibitors of certain actionsof gastrin. In the treatment of certain conditions, for exampleinflammation and inhibiting the actions of histamine on blood pressure,a combination of histamine H-1 and H-2 antagonists is useful.

Throughout the present specification, by the term "lower alkyl" we meanan alkyl group containing from 1 to 4 carbon atoms.

The compounds with which the present invention is concerned may berepresented by the following general formula:- ##STR1## wherein Het₁ andHet₂, which may be the same or different, are each a nitrogen containing5 or 6 membered heterocyclic ring such as imidazole, pyridine, thiazole,isothiazole, oxazole, isoxazole, triazole or thiadiazole, which isoptionally substituted by lower alkyl, hydroxyl, halogen or amino: Z₁and Z₂ are sulphur or a methylene group: B₁ is (CH₂)_(n).sbsb.1 and B₂is (CH₂)_(n).sbsb.2 and when Z₁ is sulphur and m₁ is 1, B₁ may also beCH₂ CHR, CHRCH₂, CHRCH₂ CH₂, CH₂ CHRCH₂ or CH₂ CH₂ CHR wherein R ismethyl or ethyl or when Z₁ and Z₂ are sulphur and m₁ and m₂ are 1, bothB₁ and B₂ may also be ##STR2## m₁ and m₂ are 0, 1 or 2 and n₁ and n₂ are2 or 3, provided that the sum of m₁ and n₁ and the sum of m₂ and n₂ arefrom 2 to 4: and X is sulphur, oxygen, or NY wherein Y is hydrogen,cyano, CONH₂ or SO₂ R₁ wherein R₁ is lower alkyl or phenyl, providedthat, when X is NH, at least one of Z, or Z₂ is sulphur, and that when Xis NH the sum of m₁ and n₁ is 3 or 4 if Het₁ is imidazole and the sum ofm₂ and n₂ is 3 or 4 if Het₂ is imidazole; or a pharmaceuticallyacceptable acid addition salt thereof.

It will be understood that the structure illustrated in Formula I isonly one of several representations and that other tautomeric forms arealso covered by the present invention.

A preferred group of compounds are those wherein B₁ is (CH₂)_(n).sbsb.1and B₂ is (CH₂)_(n).sbsb.2 and within this group it is further preferredthat Het₁ --(CH₂)_(m).sbsb.1 --Z₁ -- B₁ and Het₂ --(CH₂)_(m).sbsb.2 --Z₂--B₂ are the same. A further preference is for the sum of m₁ and n₁ andthe sum of m₂ and n₂ to be 3 or 4 and particularly preferably, m₁ and m₂are each 1 and n₁ and n₂ are each 2; compounds wherein Z₁ and Z₂ aresulphur are also preferred: it follows therefore that compounds whereinthe N-substituents are Het₁ --CH₂ S(CH₂)₂ and Het₂ --CH₂ S(CH₂)₂ are animportant part of the present invention. Het₁ and Het₂ may particularlyusefully be imidazole, thiazole, isothiazole or pyridine optionallysubstituted by methyl, hydroxyl or halogen for example they may be4-imidazolyl, 5-methyl-4-imidazolyl, 5-bromo-4-imidazolyl, 2-pyridyl,3-methyl-2-pyridyl, 3-bromo-2-pyridyl, 3-chloro-2-pyridyl, 2-thiazolyl,3-isothiazolyl, 4-chloro-3-isothiazolyl or 4-bromo-3-isothiazolyl. Auseful series of histamine H-2 antagonist compounds are those wherein Xis sulphur and, in a further useful series, X is NY and Y is hydrogen orcyano.

Examples of specific compounds having histamine H-2 antagonist activitywhich are within the scope of the present invention are:

N,n'-bis[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-thiourea,

N,n'-bis[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-N"-cyanoguanidine,

N,n'-bis[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-guanidine,

N,n'-bis[2-((2-thiazolyl)methylthio)ethyl]-N"-cyanoguanidine,

N-[2-((4-methyl-5-imidazolyl)methylthio)propyl]-N'-(2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidineand

N,n'-bis[2-((4-methyl-5-imidazolyl)methylthio)propyl]-guanidine.

The compounds of the present invention wherein X is sulphur may beproduced from an amine of the formula Het₁ --(CH₂)_(m).sbsb.1 --Z₁ --B₁--NH₂, wherein Het₁, m₁, Z₁ and B₁ have the same significance as inFormula I, by reaction thereof with carbon disulphide and a lower alkylhalide or sulphate such as methyl iodide or methyl sulphate to give thecorresponding dithiocarbamic ester of Formula II (which will of coursenormally exist in the form of the acid addition salt): ##STR3## whereinA is lower alkyl and subsequent reaction of this compound under alkalineconditions (e.g. in the presence of sodium ethoxide in a solvent such asethanol) with an amine of Formula Het₂ --(CH₂)_(m).sbsb.2 --Z₂ --B₂--NH₂. Where Het₁ --(CH₂)_(m).sbsb.1 --Z₁ --B₁ and Het₂--(CH₂)_(mS).sbsb.2 --Z₂ --B₂ are the same, the required can be producedwithout isolation of an intermediate of Formula II by the reaction ofcarbon disulphide with an excess (two moles or more) of the amine ofFormula Het₁ --(CH₂)_(m).sbsb.1 --Z₁ --B₁ --NH₂, this reaction beingconveniently carried out in a solvent such as ethanol.

Compounds of Formula I wherein X is N-Y may be produced, directly orindirectly, by reactions involving the use of a compound of Formula III:

    (a--q).sub.2 o═n--y'                                   formula iii

wherein Q is sulphur or oxygen, A is alkyl and Y' is cyano, benzoyl orSO₂ R₁, R₁ having the same significance as in Formula I.

When the compound of Formula III is reacted with an equivalent amount ofan amine of Formula Het₁ --(CH₂)_(m).sbsb.1 --Z₁ --B₁ --NH₂, theintermediate product of Formula IV: ##STR4## is formed. This reactionmay conveniently be carried out in a solvent such as ethanol at atemperature of from 20°-100° C. Reaction of this intermediate with theamine of Formula Het₂ --(CH₂)_(m).sbsb.2 --Z₂ --B₂ --NH₂, which reactionmay also be carried out in a solvent or in the absence thereof yields aproduct of Formula V: ##STR5## The above mentioned second stage of thereaction may be modified by first adding to the intermediate of FormulaV a silver salt such as silver nitrate, removing the silver methylmercaptide which is formed, and then proceeding with the reaction withthe amine Het₂ --(CH₂)_(--B) ₂ --Z₂ -B₂ --NH₂ to give the product ofFormula V. Alternatively, when Het₁ --(CH₂)_(m).sbsb.1 --Z₁ --NH₂ is thesame as Het₂ --(CH₂)_(m).sbsb.2 --Z₂ --B₂ --NH₂, a single-stage reactionmay be employed using an excess i.e. two moles or more of the amineformula Het₁ --(CH₂)_(m).sbsb.1 --Z₁ --B₁ --NH₂ for each mole of thecompound of Formula III. In this case also the reaction is convenientlycarried out in the absence of a solvent at an elevated temperature e.g.,80°-120° C., or in a solvent, e.g., in refluxing pyridine.

When, in Formula V, Y' is cyano or SO₂ R₁ the compounds are of coursewithin the scope of Formula I. Acid hydrolysis of the compounds ofFormula V wherein Y' is benzoyl or cyano yields the compounds of FormulaI wherein Y is hydrogen: mild acid hydrolysis of the compounds ofFormula VI wherein Y' is cyano yields the compounds of Formula I whereinY is CONH₂.

The compounds of Formula I wherein Y is cyano may alternatively beprepared from the compounds wherein X is sulphur by reaction of thelatter with a heavy metal salt of cyanamide such as lead, mercury orcadmium cyanamide in a solvent such as acetonitrile and/ordimethylformamide.

An alternative method which may be used for the production of compoundsof Formula I wherein Y is hydrogen commences from a thiourea of theFormula VI: ##STR6## Reaction of this compound with a lower alkyl halidesuch as methyl iodide gives the isothiourea of Formula VII: ##STR7##wherein A is lower alkyl, and reaction of this isothiourea with an amineof Formula Het₂ --(CH₂)_(m).sbsb.2 --Z₂ --B₂ --NH₂ yields the requiredcompound.

Compounds where X is oxygen and Het₁ --(CH₂)_(m).sbsb.1 --Z₁ --B₁ --NH₂and Het₂ --(CH₂)_(m).sbsb.2 --Z₂ --B₂ --NH₂ are the same may beconveniently prepared by the reaction of the amine Het₁--(CH₂)_(m).sbsb.1 --Z₁ --B₁ --NH₂ with carbonyl dimidazole e.g., byfusion at an elevated temperature, or by reflux in a solvent such asdimethylformamide.

The amines of Formulae Het₁ --(CH₂)_(m).sbsb.1 --Z₁ --B₁ --NH₂ and Het₂--(CH₂)_(m).sbsb.2 --Z₂ --B₂ --NH₂ may be produced by the reaction of acompound of Formula X:

    het--CH.sub.2 L                                            FORMULA X

wherein Het has the same significance as Het₁ and Het₂ in Formula I andL is hydroxyl, halogen or methoxy, with an aminethiol of Formula XI:

    hs--b.sup.1 --nh.sub.2                                     formula xi

wherein B¹ has the same significance as B₁ and B₂ in Formula I.

As stated above, the compounds represented by Formula I have been foundto have pharmacological activity in the animal body as antagonists tocertain actions of histamine which are not blocked by "antihistamines"such as mepyramine. For example, they have been found to inhibitselectively the histamine-stimulated secretion of gastric acid from theperfused stomachs of rats anaesthetised with urethane at doses of from0.5 to 256 micromoles per kilogram intravenously. Similarly, the actionof these compounds is demonstrated by their antagonism to the effects ofhistamine on other tissues which, according to the above-mentioned paperof Black et al., are H-2 receptors. Examples of such tissues areperfused isolated guinea-pig atrium and isolated rat uterus. Thesecompounds of this invention have also been found to inhibit thesecretion of gastric acid stimulated by pentagastrin or by food.

The level of activity found for the compounds of the present inventionis illustrated by the effective dose range in the anaesthetised rat, asmentioned above of from 0.5 to 256 micromoles per kilogram,intravenously. Many of the compounds of the present invention produce a50% inhibition in this test at a dose of from 1 to 10 micromoles perkilogram.

For therapeutic use, the pharmacologically active compounds of thepresent invention will normally be administered as a pharmaceuticalcomposition comprising as the or an essential active ingredient at leastone such compound in the basic form or in the form of an addition saltwith a pharmaceutically acceptable acid and in association with apharmaceutical carrier therefor. Such addition salts include those withhydrochloric, hydrobromic, hydriodic, sulphuric and maleic acids and mayconveniently be formed from the corresponding bases of Formula I bystandard procedures, for example by treating the base with an acid in alower alkanol or by the use of ion exchange resins to form the requiredsalt either directly from the base or from a different addition salt.

Pharmaceutical compositions comprising a pharmaceutical carrier and acompound of Formula I or a pharmaceutically acceptable acid additionsalt thereof and methods of inhibiting H-2 histamine receptors whichcomprise adminstering a compound of Formula I or a pharmaceuticallyacceptable acid addition salt thereof are also objects of thisinvention. The pharmaceutical carrier employed may be, for example,either a solid or liquid. Exemplary of solid carriers are lactose, terraalba, sucrose, talc, gelatin agar, pectin, acacia, magnesium stearate,stearic acid and the like. Exemplary of liquid carriers are syrup,peanut oil, olive oil, water and the like.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used, the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form, or in the form of a troche orlozenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg. to about 1 gm. If a liquid carrier is used,the preparation may be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid such as an ampoule, or an aqueous ornonaqueous liquid suspension.

The pharmaceutical compositions are prepared by conventional techniquesinvolving procedures such as mixing, granulating and compressing ordissolving the ingredients as appropriate to the desired preparation.

The active ingredient will be present in the composition in an effectiveamount to inhibit histamine activity. The route of administration may beorally or parenterally.

Preferably, each dosage unit will contain the active ingredient in anamount of from about 50 mg to about 250 mg. most preferably from about100 mg. to about 200 mg.

The active ingredient will preferably be administered in equal doses oneto three times per day. The daily dosage regimen will preferably be fromabout 150 mg. to about 750 mg. most preferably from about 300 mg. toabout 600 mg.

Other pharmacologically active compounds may in certain cases beincluded in the composition. Advantageously the composition will be madeup in a dosage unit form appropriate to the desired mode ofadministration, for example as a tablet, capsule or injectable solution.The invention is illustrated but in no way limited by the followingExamples:

EXAMPLE 1 N,N'-bis-[2-((4-Methyl-5-imidazolyl)methylthio)ethyl]thiourea

(a) (i) A solution of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole(10.2 g.) in ethanol (75 ml.) was added slowly, with stirring, to carbondisulphide (200 ml.). The mixture was set aside overnight at roomtemperature and the solid formed was collected and recrystallised fromaqueous isopropyl alcohol to affordN-[2-((4-methyl-5-imidazolyl)methylthio)ethyl] dithiocarbamic acid (9.8g.), m.p. 127°-129°.

(Found: C, 38.6; H, 5.5; N, 16.7% C₈ H₁₃ N₃ S₃ requires: C, 38.8; H,5.3; N, 17.0%)

(ii) Methyl iodide (4.0 g.) was added to a suspension of thedithiocarbamic acid (7.0 g.) in methanol (100 ml). After stirring atroom temperature for 1.5 hours a solution was obtained. Concentration,followed by recrystallisation of the residue from isopropylalcohol-ether gaveS-methyl-N-[2-((4-methyl-5-imidazolyl)methylthio))ethyl]dithiocarbamatehydriodide (8.6 g.), m.p. 167°- 169°.

(iii) A solution prepared fromS-methyl-N-[2-((4-methyl-5-imidazolyl)methylthio))ethyl]dithiocarbamatehydriodide (15.6 g.), 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole(6.8 g.) in ethanol (200 ml.) containing sodium (0.9 g.) was heatedunder reflux for 8 hours. Concentration followed by chromatographicpurification of the product on a column of silica gel with ethylacetate-isopropyl alcohol (5:1) as eluant gave the title compound whichwas converted to the dihydrochloride (2.5g., m.p. 115°- 120° ) withethanolic hydrogen chloride.

(Found: C, 39.1; H, 5.7; N, 17.8; S, 20.6; Cl, 15.3% C₁₅ H₂₄ N₆ S₃.2HClrequires: C, 39.4; H, 5.7; N, 18.4; S, 21.0; Cl, 15.5%)

b) A solution of 4-methyl-5-((2-aminoethyl)thiomethyl) imidazole (34.0g.) and carbon disulphide (7.6 g.) in ethanol (250 ml.) was heated underreflux for 6 hours. Concentration followed by chromatographicpurification of the product on a column of silica gel with elution byisopropyl alcohol-ethyl acetate followed by isopropyl alcohol-ethanolgave N,N'-bis-[2-(4-methyl-5-imidazolyl)methylthio)ethyl] thiourea (18g.), m.p. 133°- 135°.

(Found: C, 47.0; H, 6.1; N, 22.0%. C₁₅ H₂₄ N₆ S₃ requires: C, 46.8: H,6.3; N, 21.9%)

EXAMPLE 2 N,N'-bis-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]urea

(a) A mixture of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (8.55g.) and 1,1-carbonyl di-imidazole (2.70 g.) was heated at 100° for 1hour. Cooling and digesting with hot water gave a solid which wascollected and washed successively with ethanol, water and methanol.Recrystallisation from methanol-ether affordedN,N'-bis-[2-((4-methyl-5-imidazolylmethylthio)ethyl] urea, m.p. 225°-228°.

(Found: C, 48.6; H, 6.7; N, 22.8; S, 17.4%. C₁₅ N₂₄ N₆ O S₂ requires: C,48.9; H, 6.6; N, 22.8; S, 17.4%.

(b) A mixture of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (1.6 g.)and 1,1-carbonyl di-imidazole (0.5 g.) in dimethyl formamide (12 ml.)was heated to reflux temperature whereupon the mixture solidified. Aftercooling, a small quantity of dimethyl formamide was added and the slurrywas filtered to give the solid product which was washed with water,ethanol and ether and finally recrystallised from dimethyl formamide.Yield 0.5 g., m.p. 230°- 234°.

EXAMPLE 3 N-Cyano-N',N"-bis-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine

(a) Lead cyanamide (8.7 g.) was added to a solution ofN,N'-bis-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]thiourea inacetonitrile (100 ml.) and dimethyl formamide (20 ml.) and the resultantsuspension was heated under reflux with stirring for 24 hours.Additional lead cyanamide (8.7 g.) was added and heating was continuedfor 24 hours. Following filtration and concentration, the residue waschromotographed on a column of silica gel, eluting with ethylacetate-isopropyl alcohol (5:1). Recrystallisation from isopropylalcohol-isopropyl acetate affordedN-cyano-N',N"-bis-[2-((4-methyl-5-imidazolyl)methylthio)ethyl] guanidine(0.6 g.), m.p. 92°- 95°.

(b) A mixture of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (1.71g.) and dimethylcyanodithioimidocarbonate (0.36 g.) was heated on thesteam bath for 4 hours. The addition of acetonitrile afforded thecrystalline product (0.9 g.) m.p. 88°- 90°.

(c) A solution of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (6.8g.) and dimethylcyanodiothioimidocarbonate (1.36 g.) in pyridine (6 ml.)was heated under reflux for 7 hours. Concentration, followed bytrituration with acetonitrile afforded the crystalline product (2.0 g.),m.p. 93°- 96°.

(d) (i) A solution of 4 -methyl-5-((2-aminoethyl)thiomethyl) imidadole(23.4 g.) in ethanol was added slowly to a solution ofdimethylcyanodithioimidocarbonate (20.0 g.) in ethanol, with stirring atroom temperature. The mixture was set aside overnight at roomtemperature. Filtration affordedN-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (10.0 g.) m.p. 148°- 150°. The filtrate wasconcentrated under reduced pressure and the mixture was triturated withcold water and the solid obtained, filtered off and recrystallised twicefrom isopropyl alcohol/ether to yield further product (27 g.), m.p.148°- 150°.

(Found: C, 44.4: H, 5.6: N, 26.0: S, 24.3. C₁₀ H₁₄ N₅ S₂ requires: C,44.6: H, 5.6: N, 26.0; S, 23.8.)

(ii) A solution of silver nitrate (3.06 g.) in dimethyl formamide (20ml.) was added to a solution ofN-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea(4.9 g.) in dimethylformamide (30 ml.). The resultant solution was keptat room temperature for 1 hour cooled and filtered to remove silvermethylmercaptide, 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (3.07g.) in dimethyl formamide (10 ml.) was added and this solution washeated overnight on the steam bath. Concentration followed bychromotographic purification of the product on a column of silica gelafforded the title compound (1.2 g.), m.p. 90°- 94°, containing a smallamount of water.

(Found: C, 47.4; H, 5.9; N, 27.6; S, 15.5% C₁₆ H₂₄ N₈ S₂ + 3% H₂ Orequires: C, 47.5; H, 6.3; N, 27.7; S, 15.8%).

EXAMPLE 4 N-[2(2-Pyridylmethylthio)ethyl]-N'-[2-(4-methyl-5-imidazolylmethylthio)ethyl]thiourea dihydrochloride.

A solution preapred from S-methyl-N-[2 -((4-methyl-5-imidazolyl)methylthio))ethyl]dithiocarbamate hydriodide (7.8 g.),2-((2-aminoethyl)thiomethyl)pyridine (6.6 g.) in ethanol containingsodium (0.45 g.) was heated under reflux for 20 hours. Concentrationfollowed by chromotographic purification of the product on a column ofsilica gel gave the title compound, which was concentrated to ahygroscopic dihydrochloride

(Found: Cl, 15.4%. C₁₆ H₂₃ N₅ S₃ .2 HCl requires: Cl, 15.6%)

EXAMPLE 5N-[2-(3-Pyridylmethylthio)ethyl]-N'-[2-(4-methyl-5-imidazolylmethylthio)ethyl]thiourea

The reaction of 3-((2-aminoethyl)thiomethyl)pyridine (6.6 g.) withS-methyl-N'-[2-((4-methyl-5-imidazolylmethylthio)ethyl]dithiocarbamatehydriodide (7.8 g.) by the method described in Example 4 afforded thetitle compound as the noncrystalline base containing a small quantity ofethyl acetate.

(Found: C, 50.2; H, 6.3; N, 17.5% C₁₆ H₂₃ N₅ S₃ + 3% CH₃ COOC₂ H₅requires: C, 50.5; H, 6.2; N, 17.8%)

EXAMPLE 6 N,N'-bis-[4-4(5)-Imidazolyl butyl]thiourea

A solution of 4-(4-aminobutyl)imidazole (5.6 g.) and carbon disulphide(1.6 g.) in ethanol (60 ml.) was kept at room temperature for 2 hoursand heated under reflux for 6 hours. After concentration the residue wasprecipitated from ethanol with water and from ethanol with etheraffording the solid product (5.3 g.) which was finally recrystallisedfrom a large volume of acetonitrile to give the title compound, m.p.137°-138° .

(Found: C, 56.1; H, 7.4; N, 26.1; S, 9.8% C₁₅ H₂₄ N₆ S requires: C,56.2; H, 7.6; N, 26.2; S, 10.0%)

EXAMPLE 7N,N'-bis-[2-(3-Bromo-2-pyridylmethylthio)ethyl]-N"-cyano-guanidine

(i) A solution sodium nitrite (2.38 g.) in water (10 ml.) was addeddropwise to a stirred mixture of 3-amino-2-hydroxymethylpyridine (4.8g.) in aqueous hydrobromic acid (48%, 10 ml) and water (5 ml) at 0°-5°C. This solution of the diazonium salt was added to a hot solution ofcuprous bromide (2.5 g.) in 60% hydrobromic acid and following cessationof nitrogen evolution the mixture was heated on the steam bath for 0.5hours, diluted with water and saturated with hydrogen sulphide.Filtration, concentration to low bulk and extraction with chloroformyielded 3-bromo-2-hydroxymethyl-pyridine (4.8 g.). This was dissolved inaqueous hydrobromic acid (48%, 50 ml.), cysteamine hydrochloride (3.22g.) added and the solution obtained was heated under reflux for 6 hours.Concentration, followed by recrystallisation from aqueous ethanolafforded 2-((2-aminoethyl)-thiomethyl)-thiomethyl)-3-bromopyridinedihydrobromide (6.1 g.), m.p. 252°-254°.

(Found: C, 23.7; H, 3.4; N, 6.7; S, 7.9. C₈ H₁₁ Br N₂ S. 2HBr requires:C, 23.5; H, 3.2; N, 6.9; S, 7.8)

(ii) Reaction of dimethylcyanodithioimidocarbonate with2-((2-aminoethyl)thiomethyl)-3-bromopyridine by the procedure describedin Example 3 (d) gaveN-cyano-N'-[2-((3-bromo-2-pyridyl)methylthio)ethyl]-S-methylisothioureaand a mixture of this compound (1.4 g.) and3-bromo-2-((2-aminoethyl)thiomethyl)pyridine (2.0 g.) was heated at 140°for 6 hours. The product crystallised upon treatment with isopropylacetate and was recrystallised from aqueous isopropanol to give thetitle compound (1.1 g.), m.p. 118°-119°.

Found: C, 40.0; H, 3.8; N, 15.9; Br, 29.5; S, 11.9% C₁₈ H₂₀ N₆ Br₂ S₂requires: C, 39.7; H, 3.7; N, 15.4; Br, 29.4; S, 11.8%)

EXAMPLE 8 N,N'-bis-[2-(2-Pyridylmethylthio)ethyl]-N"-cyanoguanidine (i)

(i) The reaction of 2-((2-aminoethyl)thiomethyl)pyridine withdimethylcyanodithioimidocarbonate by a method similar to that describedin Example (3d) affordedN-cyano-N'-[(2-(2-pyridylmethylthio)ethyl]-S-methylisothiourea, m.p.85 - 88°. (from isopropyl alcohol-ether)

(Found: C, 49.6; H, 5.4; N, 21.0; S, 24.0% C₁₁ H₁₄ N₄ S₂ requires: C,49.6; H, 5.3; N, 21.0; S, 24.1%

(ii) The reaction ofN-cyano-N'-[2-(2-pyridylmethylthio)ethyl]-S-methylisothiourea with2-((2-aminoethyl)pyridine by the method described in Example 7 affordedthe title compound m.p. 78°-80°.

(Found: C, 56.2; H, 5.7; N, 21.9; S, 16.5%. C₁₈ H₂₂ N₆ S₂ requires: C,55.9; H, 5.7; N, 21.7; S, 16.6%)

EXAMPLE 9 N,N'-bis-[2-(2-Thiazolylmethylthio)ethyl]-N"-cyanoguandine

A solution of 2-((2-aminoethyl)thiomethyl)thiazole (1.74 g.) anddimethylcyanodithioimidiocarbonate (0.68 g.) in pyridine (10 ml.) washeated on the steam bath for 6 hours and at reflux temperature for 6hours. Additional amine (0.3 g.) was added and heating was continued atreflux temperature for a further period of 6 hours. Concentrationfollowed by chromatographic purification on a column of silica gelafforded the title compound (0.25 g.), m.p. 66°-68°.

(Found; C, 42.0; H, 4.6; N, 21.0%. C₁₄ H₁₈ N₆ S₄ requires: C, 42.2; H,4.6; N, 21.1%)

EXAMPLE 10 N,N'-bis-[2-(4-Methyl-5-imidazolyl)methylthio)ethyl]guanidinesulphate

(i) A solution of N-[2-((4-methyl-5-imidazolyl)methylthio)ethylthiourea(2.29 g.) and methyl iodide (1.56 g.) in methanol (5 ml) was kept atroom temperature for 18 hours affordingS-methyl-N-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]thiouroniumiodide (2.3g.), m.p. 128°-131°. The iodide was concentrated to thecorresponding sulphate by ion-exchange on an ion-exchange resin (IRA401) in the sulphate form.

(ii) A solution of the thiouronium sulphate (20.0 g.) and4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (9.2 g.) in water washeated under reflux for two hours. Concentration followed byrecrystallisation from ethanol-methanol afforded the title compound (9.8g.), m.p. 138°-139°.

(Found: C, 42.8; H, 6.2; N, 23.1; S, 18.9% C₁₅ H₂₅ N₇ S₂.1/2 H₂ SO₄requires: C, 43.2; H, 6.3; N, 23.5; S, 19.2%)

EXAMPLE 11N-[2-((4-Methyl-5-imidazolyl)methylthio)ethyl]-N'-[4-(4-imidazolyl)butyl]guanidinetrihydrochloride

A solution ofS-methyl-N-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]thiouroniumsulphate (2.93 g.) and 4-(4-aminobutyl) imidazole (1.39 g.) in water (10ml) was heated under reflux for 3 hours. Following concentration, theresidue was converted to the free base with an ion-exchange resin (IRA401) in the OH-form and then applied to a weakly acidic cation exchangeresin (C 6 50) in the H+form and eluted with dilute hydrochloric acid.The eluate was concentrated and the residue crystallised withethanol-ether to yield the title compound (1.9 g.) m.p. 170°-172°.

Found: S, 23.8%. C₁₅ H₂₅ N₇ S . 3HCl requires = S, 23.9%)

EXAMPLE 12 N,N'-bis-[2-(2-Thiazolylmethylthio)ethyl]guanidinetrihydrochloride

A solution of 2-((2-aminoethyl)thiomethyl)thiazole (from thedihydrobromide, 5.0 g.) and N-benzoyl-bis-dimethylthio imidocarbonate(1.7 g.) in pyridine (10 ml.) was heated at 100° for 6 hours. Followingconcentration, the residue was extracted with ether and theether-extract concentrated to an oil which was chromatographed on acolumn of silica gel. Elution by ethyl acetate afforded N-benzoyl-N',N"-bis-[2-((2-thiazolyl)methylthio)ethyl]guanidine (1.8 g.). This washydrolysed with hydrochloric acid at steam bath temperature for 10 hoursand concentrated. The residue was extracted with ether andrecrystallised from ethanol-methanol-ether to give the title compound ascolourless needles (1.4 g.), m.p 176°-178°.

Found: C, 32.1; H, 4.6; N, 14.2; Cl, 21.8%. C₁₃ H₁₉ N₅ S₄ . HClrequires: C, 32.3; H, 4.6; N, 14.5; Cl, 22.0%)

EXAMPLE 13N-Benzenesulphonyl-N-N"-bis-[2-((4-methyl-5-imidazolyl)-methylthio)ethyl]guanidine

A mixture of 4-methyl-5-((2-aminoethyl)thiomethyl)-imidazole (4.7 g.)and N-benzenesulphonyl-bis-dimethylthioimidocarbonate (3.6 g.) washeated at 140°- 150° for one hour. The product was chromatographed on acolumn of silica gel with elution by ethyl acetate-ethanol (3:2) to givethe product as a glass (5.5 g.) containing a small quantity of ethanol.

(Found: C, 49.6; H, 5.8; S, 18.3% C₂₁ H₂₉ N₇ O₂ S₃ + 1% EtOH requires:C, 49.7; H, 5.8; S, 18.7%)

EXAMPLE 14N-Cyano-N'-[3-(4-imidazolyl)propyl]-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine

The reaction ofN-cyano-N'-[2-((4-methyl-5-imidazolyl)-methylthio)ethyl]-S-methylisothiourea(3.5 g), with excess 4-(3-aminopropyl)imidazole (5.0 g) at 120°-130°afforded the title compound (1.7 g) m.p. 140°-142° (from isopropylalcohol-ether).

(Found: C, 51.8; H, 6.5; N, 32.1; S, 9.2% C₁₅ H₂₂ N₈ S requires: C,52.0; H, 6.4; N, 32.3; S, 9.3%)

EXAMPLE 15N,N'-bis-[2-((4-Bromo-5-imidazolyl)methylthio)ethyl]-guanidine

The reaction of 4-bromo-5-[(2-aminoethyl)thiomethyl]-imidazole (from thedihydrobromide, 5.4 g) with N-benzoyl-bis-dimethylthioimidocarbonate(1.54 g.) in pyridine by the method described in Example 12 gaveN-benzoyl-N',N"-bis-[2-((4-bromo-5-imidazolyl)methylthio)ethyl]guanidineas needles, m.p. 105°-110° (from ethanol-ether). Acid hydrolysis by themethod described in Example 12 gave the title compound as an amorphoussolid.

EXAMPLE 16 N,N'-bis[2-((3-bromo-2-pyridyl)methylthio)ethyl]-guanidine

The reaction of 3-bromo-2-[(2-aminoethyl)thiomethyl]-pyridine withN-benzoyl-bis-dimethylthioimidocarbonate in pyridine by the methoddescribed in Example 12 yieldedN-benzoyl-N',N"-bis-[2-((3-bromo-2-pyridyl)-methylthio)ethyl]guanidinewhich, on acid hydrolysis, yielded the title compound.

EXAMPLE 17N-Cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-N"-[2-(2-thiazolylmethylthio)ethyl]guanidine

Reaction of dimethylcyanodithioimidocarbonate with2-[(2-aminoethyl)thiomethyl]thiazole by the method described in Example3(d) gaveN-cyano-N'-[2-(2-thiazolylmethylthio)ethyl]-S-methylisothiourea. Fusionof this compound (2.15 g) with4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (2.02 g) on the steambath for 6 hours, followed by chromatographic purification on a columnof silica gel with ethyl acetate/isopropyl alcohol (5:1) as eluantafforded the title compound.

(Found: C, 45.7; H, 5.4; N, 24.5% C₁₅ H₂₁ N₇ S₃ requires: C, 45.5; H,5.4; N, 24.8%)

EXAMPLE 18N-Carbamoyl-N',N"-bis-[2-((4-methyl-5-imidazolyl)-methylthio)ethyl]guanidine

Treatment ofN-cyano-N',N"-bis-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidinewith ethanolic hydrogen chloride for 70 hours at room temperature,followed by basification and purification of the base on a column ofsilica gel with elution by ethanol followed by methanol afforded thetitle compound as an amorphous solid having m.p. 60°-70°.

(Found: C, 46.3; H, 6.4; N, 26.1% C₁₆ H₂₆ N₈ OS₂ requires: C, 46.8; H,6.4; N, 27.2%)

EXAMPLE 19 N,N"-bis[2-((3-chloro-2-pyridyl)methylthio)ethyl]-guanidine

(i) A solution sodium nitrite (2.38 g) in water (10ml) was addeddropwise to a stirred mixture of 3-amino-2-hydroxymethylpyridine (4.8 g)in aqueous hydrochloric acid (48% 10 ml) and water (5 ml) at 0°-5° C.This solution of the diazonium salt was added to a hot solution ofcuprous chloride (2.5 g) in conc. hydrochloric acid and followingcessation of nitrogen evolution the mixture was heated on the steam bathfor 0.5 hours, diluted with water and saturated with hydrogen sulphide.Filtration, concentration to low bulk and extraction with chloroformyielded 3-chloro-2-hydroxymethylpyridine (3.7 g), m.p. 42°-44° (fromn-pentane). This was dissolved in aqueous hydrobromic acid (48% 50 ml),cysteamine hydrochloride (3.22 g) added and the solution obtained washeated under reflux for 6 hours. Concentration, followed byrecrystallisation from aqueous ethanol afforded2-[(2-aminoethyl)-thiomethyl]-3-chloropyridine dihydrobromide (6.0 g),m.p. 250° .

(ii) Reaction of the free base derived from the above dihydrobromidewith N-benzoyl-bis-dimethylthioimidocarbonate in the procedure ofExample 16 yields the title compound.

EXAMPLE 20

Reaction ofS-methyl-N-[2-((4-methyl-5-imidazolyl)-methylthio)ethyl]thiouroniumsulphate with 2-[(2-aminoethyl)thiomethyl]thiazole by the procedure ofExample 10 (ii) yielded N-[2-((4-methyl-5-imidazolyl)-methylthio)ethyl]-N'-[2-(2-thiazolylmethylthio)ethyl] -guanidine.

When, in the above procedure, 2-[(2-aminoethyl)thiomethyl]thiazole isreplaced by 3-bromo-2[(2-aminoethyl)-thiomethyl]pyridine and2-(3-aminopropyl)thiazole the products are, respectivelyN-[2-((4-methyl-5-imidazolyl)-methylthio)ethyl]-N'-[2-((3-bromo-2-pyridyl)methylthio)-ethyl]guanidine,m.p. 145°-147° (tripicrolonate), andN-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-N'-[3-(2-thiazolyl)propyl]guanidine,m.p. 149°-151° C. (tripicrate).

EXAMPLE 21

A mixture of 3-[(2-aminoethyl)thiomethyl]isothiazole anddimethylcyanodithioimidocarbonate was reacted according to the procedureof Example 3(b) and resulted in the production ofN-cyano-N,N"-bis-[2-(3-isothiazolylmethylthio)ethyl]guanidine.

When the following compounds are reacted according to the aboveprocedure with dimethylcyanodithioimidocarbonate

2-[(2-aminoethyl)thiomethyl]-3-methylpyridine,

4-(3-aminopropyl)imidazole,

2-(4-aminobutyl)thiazole,

3-[(2-aminoethyl)thiomethyl]isoxazole,

3-[(2-aminoethyl)thiomethyl]-1,2,4-triazole,

2-[(2-aminoethyl)thiomethyl]-5-amino-1,3,4-thiadiazole and

2-[(2-aminoethyl)thiomethyl]-3-hydroxy-pyridine, the resulting productsare respectively as follows:

N-cyano-N',N"-bis-[2-((3-methyl-2-pyridyl)methylthio)ethyl]guanidine,m.p. 135°-137° C.,

N-cyano-N',N"-bis-3-(4-imidazolyl)propyl]-guanidine, m.p. 116°-118° C.,

N-cyano-N',N"-bis-[4-(2-thiazolyl)butyl]-guanidine, m.p. 59°-61° C.,

N-cyano-N',N"-bis-[2-(3-isoxazolylmethylthio)-ethyl]guanidine,

N-cyano-N',N"-bis-[2-(3-1,2,4-triazolylmethylthio)-ethyl]guanidine,

N-cyano-N',N"-bis-[2-((5-amino-2-1,3,4-thiadiazolyl)-methylthio)ethyl]guanidineand

N-cyano-N' ,N"-bis-[2-((3-hydroxy-2-pyridyl)methylthio)ethyl]guanidine.

EXAMPLE 22

Reaction of 2-(3-aminopropyl)oxazole anddimethylcyano-dithiomideo-carbonate according to the procedure ofExample 3(b) yieldedN-cyano-N',N"-bis-[3-(2-oxazolyl)thiopropyl]guanidine.

EXAMPLE 23

When 4-[2-(2-aminoethyl)thioethyl]imidazole is reacted withdimethylcyanodithioimidocarbonate according to the procedure of Example3(b), the resultant product isN-cyano-N',N"-bis-[2-(2-(4-imidazolyl)ethyl)thioethyl]-guanidine.

EXAMPLE 24

In the procedure of Example 1(b) using as starting materials carbondisulphide and 3-[(2-aminoethyl)-thiomethyl]isoxazole or2-[(2-aminoethyl)thiomethyl]-3-hydroxy-pyridine, the products which areobtained are respectively,N,N'-bis-[2(3-isoxazolylmethylthio)-ethyl]thiourea andN,N'-[2-((3-hydroxy-2-pyridyl)-methylthio)ethyl]thiourea.

EXAMPLE 25

Reaction of N-benzoyl-bis-dimethylthioimidocarbonate with3-[(2-aminoethyl)thiomethyl]isoxazole or2-[(2-aminoethyl)thiomethyl]-3-hydroxy-pyridine and hydrolysis of theresultant benzoyl derivative according to Example 12 resulted in theproduction of N,N'-bis-[2-(3-isoxazolylmethylthio)ethyl]guanidine andN,N'-bis-[2-((3-hydroxy-2-pyridyl)methylthio)ethyl]guanidinerespectively.

EXAMPLE 26

4-Methyl-5-[(2-aminoethyl)thiomethyl]imidazole andN-methanesulphonyl-bis-dimethylthioimidocarbonate are reacted togetheraccording to the process of Example 13 to give as the productN-methanesulphonyl-N',N"-bis-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine.

EXAMPLE 27

    ______________________________________                                        Ingredients              Amounts                                              N,N'-bis-[2-((4-Methyl-5-imidazolyl)-                                         methylthio)ethyl]thiourea                                                                              150 mg.                                              Sucrose                  75 mg.                                               Starch                   25 mg.                                               Talc                     5 mg.                                                Stearic Acid             2 mg.                                                ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatinecapsule.

EXAMPLE 28

    ______________________________________                                        Ingredients              Amounts                                              N,N'-bis-[2-((4-Methyl-5-imidazolyl)-                                         methylthio)ethyl]guanidine                                                                             200 mg.                                              Lactose                  100 mg.                                              ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatinecapsule.

EXAMPLE 29N-[2-(4-Methyl-5-imidazolylmethylthio)ethyl]-N'-[2-(4-methyl-5-imidazolylmethylthio)propyl]guanidine-trihydrochloride

(i) A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride (14.8g) and 2-mercaptopropylamine hydrochloride (12.8 g) in aqueoushydrobromic acid (48%, 100 ml) was heated under reflux for 6 hours,concentrated and recrystallised from ethanol-ether to give4-methyl-5-[(2-aminopropyl)thiomethyl]imidazole dihydrobromide (30.0 g),m.p. 177°-178°.

(ii) A solution ofN-[2-((5-methyl-4-imidazolyl)-methylthio)ethyl]thiourea (2.29 g) andmethyl iodide (1.56 g) in methanol (5 ml) was kept at room temperaturefor 18 hours affordingS-methyl-N-[2-((5-methyl-4-imidazolyl)methylthio)ethyl] thiouroniumiodide (2.3 g), m.p. 128°-131°. The iodide was converted into thecorresponding sulphate by ion-exchange resin (IRA 401) in the sulphateform.

(iii) A solution of 4-methyl-5-[(2-aminopropyl)thiomethyl]imidazole (4.0g., from the dihydrobromide) andS-methyl-N-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]thiouroniumsulphate (3.35 g) in water (25 ml) was heated under reflux for 4 hours.Concentration, followed by purification on ion-exchange resin C.G.50(H⁺), with elution by 0.02N hydrochloric acid, treatment with sodiumhydroxide and picrolonic acid affordedN-[2-(4-methyl-5-imidazolylmethylthio)ethyl]-N'-[2-(4-methyl-5-imidazolylmethylthio)propyl]guanidinetripicrolonate (1.75 g, m.p. 173°-175°, from aqueous dimethylformamide).

(Found: C, 46.9: H, 4.5: N, 21.9: S, 5.1% C₁₆ H₂₇ N₇ S₂ 3 C₁₀ H₈ N₄ O₅requires: C, 47.1; H, 4.4: N, 22.7; S, 5.5%)

The tripicrolonate was suspended in aqueous ethanol and treated withion-exchange resin IRA 400 (Cl⁻) and acidified with the hydrochloricacid to form the corresponding trihydrochloride salt.

(Found: Cl, 22.1% C₁₆ H₂₇ N₇ S₂ . 3 HCl requires: Cl, 21.7%)

EXAMPLE 30N,N'-bis-[2-(4-Methyl-5-imidazolylmethylthio)propyl]-guanidine

(i) A solution of 4-methyl-5-[(2-aminopropyl)-thiomethyl]imidazole (fromthe dihydrobromide, 13.0 g) in ethanol (50 ml) was cooled to 0° andstirred during the gradual addition of benzoylimino dichloromethane(3.78 g). After addition the reaction mixture was set aside at roomtemperature for 2 hours and heated on the steam bath for 0.5 hours.Following addition to water and removal of insoluble material byfiltration, the filtrate was adjusted to pH 9. The crude productobtained was purified by chromatography on a column of alumina followedby chromatographic purification on a column of silica gel(chloroform-methanol) to giveN-benzoyl-N',N"-bis-[2-(4-methyl-5-imidazolylmethylthio)propyl]-guanidine.

(ii) The benzoyl compound (3.2 g) was hydrolysed in concentratedhydrochloric acid (40 ml) at steam bath temperature for 5 hours.Following cooling, dilution with water and extraction with ether toremove benzoic acid, the product was purified as in Example 1 andconcentrated to the picrolonate (1.35 g), m.p. 230° (decomp).

The picrolonate was dissolved in aqueous methanol and treated withion-exchange resin IRA 401 (Cl⁻) and acidified with hydrochloric acid togive N,N'-bis-[2-(4-methyl-5-imidazolylmethylthio)propyl]-guanidinetrihydrochloride.

The NMR spectrum of a solution in D₂ O recorded at 100 mHz showed thefollowing resonances:

    ______________________________________                                        imidazole-2H                                                                             :    singlet δ 8.60                                                                          integral 2.0 protons                                                          calculated 2.0 protons                        imidazole-CH.sub.2                                                                       :    singlet δ 3.94                                                                          integral 4.4 protons                                                          calculated 4.0 protons                        NHCH.sub.2 :    doublet δ 3.39                                                                          integral 6.6 protons                           ##STR8##  :    multiplet δ 3.04                                                                        calculated 6.0 protons                        imidazole-CH.sub.3                                                                       :    singlet δ 2.37                                                                          integral 6.0 protons                                                          (internal standard)                            ##STR9##  :    doublet δ 1.34                                          ______________________________________                                    

EXAMPLE 31N-[1-((4-Methyl-5-imidazolyl)methylthio)but-2-yl]-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine

Reaction of 4-hydroxymethyl-5-methylimidazole and1-mercapto-2-aminobutane in the procedure of Example 1(i) yields4-methyl-5-[(2-aminobutyl)thiomethyl]imidazole and, when this is reactedwith S-methyl-N'-[2-((4-methyl 5-imidazolyl)methylthio)ethyl]thiouroniumsulphate in the procedure of Example 1(iii), the title compound isproduced.

EXAMPLE 32

When the following compounds are substituted for4-hydroxymethyl-5-methylimidazole in the procedure of Example 29(i):

4-hydroxymethyl-5-bromoimidazole,

2-hydroxymethyl-3-hydroxypyridine,

2-hydroxymethyl-3-chloropyridine,

2-hydroxymethylthiazole and

3-hydroxymethylisothiazole the products are, respectively:

5-bromo-4-[(2-aminopropyl)thiomethyl]imidazole dihydrobromide,

3-hydroxy-2-[(2-aminopropyl)thiomethyl]pyridine dihydrobromide,

3-chlor-2-[(2-aminopropyl)thiomethyl]pyridine dihydrobromide,

2-[(2-aminopropyl)thiomethyl]thiazole dihydrobromide and

3-[(2-aminopropyl)thiomethyl]isothiazole dihydrobromide

and when these compounds are reacted withS-methyl-N-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]thiouroniumsulphate in the procedure of Example 1 (iii) the products are,respectively:

N-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-N'-[2-((4-bromo-5-imidazolyl)methylthio)propyl]-guanidine,

N-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-N'-[2-((3-hydroxy-2-pyridyl)methylthio)propyl]-guanidine,

N-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-N'-[2-((3-chloro-2-pyridyl)methylthio)propyl]-guanidine,

N-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-N'-[2-((2-thiazolyl)methylthio)propyl]guanidineand

N-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-N'-[2-((3-isothiazolyl)methylthio)propyl]guanidine.

EXAMPLE 33

When the following compounds (obtained from the dihydrobromidesdescribed in Example 32) are substituted for4-methyl-5-[(2-aminopropyl)thiomethyl]imidazole in the procedure ofExample 30:

5-bromo-4-[(2-aminopropyl)thiomethyl]imidazole,

3-hydroxy-2-[(2-aminopropyl)thiomethyl]pyridine,

3-chloro-2-[(2-aminopropyl)thiomethyl]pyridine,

2-[(2-aminopropyl)thiomethyl]thiazole and

3-(2-aminopropyl)thiomethyl]isothiazole

the products are, respectively:

N,n'-bis-[2-((4-bromo-5-imidazolyl)methylthio)-propyl]guanidine,

N,n'-bis-[2-((3-hydroxy-2-pyridyl)methylthio)-propyl]guanidine,

N,n'-bis-[2-((3-chloro-2-pyridyl)methylthio)-propyl]guanidine,

N,n'-bis-[2-((2-thiazolyl)methylthio)propyl]-guanidine and

N,n'-bis-[2-((3-isothiazolyl)methylthod)propyl]-guanidine.

What we claim is:
 1. A compound of the formula: ##STR10## wherein Het₁and Het₂, which may be the same or different, are imidazole which isattached at a ring carbon and which is optionally substituted by loweralkyl or halogen; Z₁ and Z₂ are sulphur or a methylene group; B₁ is(CH₂)_(n).sbsb.1 and B₂ is (CH₂)_(n).sbsb.2 ; m₁ and m₂ are 0, 1 or 2and n₁ and n₂ are 2 or 3, provided that the sum of m₁ and n₁ and the sumof m₂ and n₂ are from 2 to 4; and X is sulphur, oxygen or NY wherein Yis hydrogen, cyano, CONH₂ or SO₂ R₁ wherein R₁ is lower alkyl or phenyl,provided that when X is NH, at least one of Z₁ and Z₂ is sulphur, andthat when X is NH the sum of m₁ and n₁ is 3 or 4 and the sum of m₂ andn₂ is 3 or 4, or a pharmaceutically acceptable acid addition saltthereof.
 2. A compound of claim 1 wherein Het₁ and Het₂ are imidazole.3. A compound of claim 1 wherein Het₁ and Het₂ are imidazole optionallysubstituted by methyl or halogen.
 4. A compound of claim 3 wherein Het₁and Het₂ are 4-imidazolyl, 5-methyl-4-imidazolyl or5-bromo-4-imidazolyl.
 5. A compound of claim 1 wherein Het₁--(CH₂)_(m).sbsb.1 --Z₁ --B₁ and Het₂ --(CH₂)_(n).sbsb.2 --Z₂ --B₂ arethe same.
 6. A compound of claim 1 wherein the sum of m₁ and n₁ or m₂and n₂ is 3 or
 4. 7. A compound of claim 6 wherein m₁ and m₂ are 1 andn₁ and n₂ are
 2. 8. A compound of claim 1 wherein Z₁ and Z₂ are sulphur.9. A compound of claim 1 wherein X is sulphur or N-Y wherein Y ishydrogen or cyano.
 10. A compound of claim 1, said compound beingN,N'bis-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-thiourea.
 11. Acompound of claim 1, said compound beingN,N'-bis-[2-((4-methyl-5-imidazolyl)methylthio)-ethyl]-N"-cyano-guanidine.12. A compound of claim 1, said compound beingN,N'-bis-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-guanidine.
 13. Apharmaceutical composition to inhibit H-2 histamine receptors comprisinga pharmaceutical carrier and in an effective amount to inhibit saidreceptors a compound of claim
 1. 14. A method of inhibiting H-2histamine receptors which comprises administering to an animal in aneffective amount to inhibit said receptors a compound of claim 1.